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- PDB-5i0l: Crystal structure of the catalytic domain of MMP-12 in complex wi... -

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Basic information

Entry
Database: PDB / ID: 5i0l
TitleCrystal structure of the catalytic domain of MMP-12 in complex with a selective sugar-conjugated arylsulfonamide carboxylate water-soluble inhibitor (DC27).
ComponentsMacrophage metalloelastase
KeywordsHYDROLASE / Inhibitor / complex / glycoconjugate / metalloprotease
Function / homology
Function and homology information


macrophage elastase / negative regulation of endothelial cell-matrix adhesion / bronchiole development / positive regulation of epithelial cell proliferation involved in wound healing / elastin catabolic process / regulation of defense response to virus by host / positive regulation of type I interferon-mediated signaling pathway / wound healing, spreading of epidermal cells / negative regulation of type I interferon-mediated signaling pathway / lung alveolus development ...macrophage elastase / negative regulation of endothelial cell-matrix adhesion / bronchiole development / positive regulation of epithelial cell proliferation involved in wound healing / elastin catabolic process / regulation of defense response to virus by host / positive regulation of type I interferon-mediated signaling pathway / wound healing, spreading of epidermal cells / negative regulation of type I interferon-mediated signaling pathway / lung alveolus development / Collagen degradation / response to amyloid-beta / collagen catabolic process / positive regulation of interferon-alpha production / extracellular matrix disassembly / core promoter sequence-specific DNA binding / collagen binding / Degradation of the extracellular matrix / extracellular matrix organization / metalloendopeptidase activity / cellular response to virus / extracellular matrix / protein import into nucleus / endopeptidase activity / sequence-specific DNA binding / serine-type endopeptidase activity / calcium ion binding / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / proteolysis / extracellular space / extracellular region / zinc ion binding / nucleus / cytoplasm
Similarity search - Function
Hemopexin, conserved site / Hemopexin domain signature. / Hemopexin-like domain / Peptidase M10A, cysteine switch, zinc binding site / Matrixins cysteine switch. / Peptidoglycan binding-like / Hemopexin-like repeats / Hemopexin-like domain superfamily / Hemopexin / Hemopexin repeat profile. ...Hemopexin, conserved site / Hemopexin domain signature. / Hemopexin-like domain / Peptidase M10A, cysteine switch, zinc binding site / Matrixins cysteine switch. / Peptidoglycan binding-like / Hemopexin-like repeats / Hemopexin-like domain superfamily / Hemopexin / Hemopexin repeat profile. / Hemopexin-like repeats. / Peptidase M10A / Peptidase M10A, catalytic domain / Putative peptidoglycan binding domain / Peptidase M10, metallopeptidase / Matrixin / PGBD-like superfamily / Peptidase, metallopeptidase / Zinc-dependent metalloprotease / Collagenase (Catalytic Domain) / Collagenase (Catalytic Domain) / Metallopeptidase, catalytic domain superfamily / Neutral zinc metallopeptidases, zinc-binding region signature. / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-H27 / DI(HYDROXYETHYL)ETHER / S-1,2-PROPANEDIOL / Macrophage metalloelastase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.45 Å
AuthorsStura, E.A. / Rosalia, L. / Cuffaro, D. / Tepshi, L. / Ciccone, L. / Rossello, A.
CitationJournal: Chemmedchem / Year: 2016
Title: Sugar-Based Arylsulfonamide Carboxylates as Selective and Water-Soluble Matrix Metalloproteinase-12 Inhibitors.
Authors: Nuti, E. / Cuffaro, D. / D'Andrea, F. / Rosalia, L. / Tepshi, L. / Fabbi, M. / Carbotti, G. / Ferrini, S. / Santamaria, S. / Camodeca, C. / Ciccone, L. / Orlandini, E. / Nencetti, S. / ...Authors: Nuti, E. / Cuffaro, D. / D'Andrea, F. / Rosalia, L. / Tepshi, L. / Fabbi, M. / Carbotti, G. / Ferrini, S. / Santamaria, S. / Camodeca, C. / Ciccone, L. / Orlandini, E. / Nencetti, S. / Stura, E.A. / Dive, V. / Rossello, A.
History
DepositionFeb 4, 2016Deposition site: RCSB / Processing site: PDBE
Revision 1.0Jul 6, 2016Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2016Group: Database references
Revision 1.2Aug 17, 2016Group: Database references
Revision 1.3Jan 10, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Macrophage metalloelastase
B: Macrophage metalloelastase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,70620
Polymers35,2312
Non-polymers2,47418
Water5,459303
1
A: Macrophage metalloelastase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,87410
Polymers17,6161
Non-polymers1,2589
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Macrophage metalloelastase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,83210
Polymers17,6161
Non-polymers1,2169
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)39.090, 62.860, 63.750
Angle α, β, γ (deg.)90.00, 102.54, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Macrophage metalloelastase / MME / Macrophage elastase / hME / Matrix metalloproteinase-12 / MMP-12


Mass: 17615.670 Da / Num. of mol.: 2 / Fragment: UNP residues 106-263 / Mutation: F171D
Source method: isolated from a genetically manipulated source
Details: catalytic domain of MMP-12 with F171D mutation. / Source: (gene. exp.) Homo sapiens (human) / Tissue: macrophage / Gene: MMP12, HME / Details (production host): propagated in E.C. XL1-Blue / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): star / References: UniProt: P39900, macrophage elastase

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Non-polymers , 8 types, 321 molecules

#2: Chemical ChemComp-H27 / (2R)-2-[{(E)-2-[({(2R,3R,4R,5S,6R)-3-(acetylamino)-4,5-bis(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-2-yl}carbamothioyl)amino]ethenyl}(biphenyl-4-ylsulfonyl)amino]-3-methylbutanoic acid


Mass: 762.847 Da / Num. of mol.: 2 / Mutation: F171D
Source method: isolated from a genetically manipulated source
Formula: C34H42N4O12S2 / Details: catalytic domain of MMP-12 with F171D mutation. / Source: (gene. exp.) Homo sapiens (human) / Tissue: macrophage / Details (production host): propagated in E.C. XL1-Blue / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): star / References: macrophage elastase
#3: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#4: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Ca
#5: Chemical ChemComp-PGO / S-1,2-PROPANEDIOL


Mass: 76.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O2
#6: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#7: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#8: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 303 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.15 Å3/Da / Density % sol: 42.82 % / Description: thin plates
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: Protein-inhibitor complex: hMMP12 0.631 milli-M + 0.010 M Acetohydroxamic acid + 0.005 M inhibitor DC27, 10% DMSO. precipitant: 34% PEG 4K, 1.5 M imidazole piperidine, pH 8.5, Dioxane 25% ...Details: Protein-inhibitor complex: hMMP12 0.631 milli-M + 0.010 M Acetohydroxamic acid + 0.005 M inhibitor DC27, 10% DMSO. precipitant: 34% PEG 4K, 1.5 M imidazole piperidine, pH 8.5, Dioxane 25% Cryoprotectant: 40% Cryomix: (12.5 % diethylene glycol + 12.5 % glycerol + 12.5 % 1,2-propanediol + 12.5 % 2,3-butanediol + 25 % DMSO + 30 % 1,4-dioxane), 25% MPEG 6K, 0.1 M AAB (Na acetate, ADA, Bicine: 10% acid/90% basic), pH 8.5
Temp details: cooled incubator

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Data collection

DiffractionMean temperature: 100 K / Ambient temp details: cryonozzle
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: MASSIF-1 / Wavelength: 0.965 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jan 29, 2015 / Details: Mirrors
RadiationMonochromator: Single Silicon (111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.965 Å / Relative weight: 1
ReflectionResolution: 2.45→45 Å / Num. obs: 11195 / % possible obs: 99.2 % / Observed criterion σ(I): -3 / Redundancy: 3.14 % / Biso Wilson estimate: 28.91 Å2 / Rmerge(I) obs: 0.111 / Rsym value: 0.093 / Net I/σ(I): 9.6
Reflection shellResolution: 2.45→2.51 Å / Redundancy: 3.23 % / Rmerge(I) obs: 0.23 / Mean I/σ(I) obs: 5.23 / % possible all: 99.3

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
XDSdata reduction
XSCALEdata scaling
REFMACphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4H84

4h84


Resolution: 2.45→44.22 Å / SU ML: 0.38 / Cross valid method: THROUGHOUT / σ(F): 1.05 / Phase error: 29.36
RfactorNum. reflection% reflection
Rfree0.253 555 5.01 %
Rwork0.175 --
obs0.179 11075 99 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.45→44.22 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2484 0 142 303 2929
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0152766
X-RAY DIFFRACTIONf_angle_d1.7543757
X-RAY DIFFRACTIONf_dihedral_angle_d18.48975
X-RAY DIFFRACTIONf_chiral_restr0.123381
X-RAY DIFFRACTIONf_plane_restr0.009494
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.45-2.69650.3421360.2492575X-RAY DIFFRACTION99
2.6965-3.08670.27061380.17182621X-RAY DIFFRACTION99
3.0867-3.88850.23341400.14762656X-RAY DIFFRACTION100
3.8885-44.23120.22961410.17182668X-RAY DIFFRACTION99
Refinement TLS params.Method: refined / Origin x: 10.3639 Å / Origin y: 15.2171 Å / Origin z: 14.5706 Å
111213212223313233
T0.062 Å2-0.037 Å2-0.0006 Å2-0.0598 Å20.0031 Å2--0.0583 Å2
L0.0141 °2-0.0063 °20.0098 °2-0.02 °2-0.0004 °2--0.0121 °2
S-0.0214 Å °-0.0337 Å °0.0021 Å °-0.0135 Å °0.0692 Å °0.0284 Å °0.0018 Å °0.0018 Å °-0 Å °
Refinement TLS groupSelection details: ALL

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